Primary Gastrointestinal Non-Hodgkin s Lymphoma: A Retrospective Study with Emphasis on Prognostic Factors and Treatment Outcome

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1 Journal of the Egyptian Nat. Cancer Inst., Vol.,, December: -, 8 Primary Gastrointestinal Non-Hodgkin s Lymphoma: A Retrospective Study with Emphasis on Prognostic Factors and Treatment Outcome HANAN SHAWKY, M.D. and HESHAM TAWFIK, M.D. The Department of Clinical Oncology, Faculty of Medicine, Tanta University Hospital. ABSTRACT Purpose: The study was initiated to obtain epidemiologic data and information on anatomic and histologic distribution, clinical features, prognostic factors and treatment results in patients with primary gastrointestinal non-hodgkin s lymphomas (PGI NHL). Patients and Methods: We carried out analysis of 8 patients of PGI NHL during the time period from January 997 to January 7 at the Clinical Oncology Department, Tanta University Hospital to evaluate clinical features and treatment outcome. Results: A total of 7. of patients had gastric NHL (PGL). Within the intestine, the small bowel and the ileocecal region were involved in 8. and 7. of the cases, respectively. Multiple gastrointestinal (MGI) involvement was in.. Approximately 8 of the PGI NHL were in stages IE/IIE. Forty percent of PGL were of low-grade mucosa-associated lymphatic tissue (MALT) type. Most intestinal NHL were of high grade NHL. The median follow-up time was 89. months. The site of origin, disease stage, complete resection of the tumor and histologic grade were the most important significant prognostic factors affecting disease-free (DFS) and overall survivals (OS). Numbers in intestinal lymphomas were too small for subanalyses. The OS and DFS after years were 78. and 7. respectively in all patients with PGI NHL. Conclusion: Primary gastrointestinal non-hodgkin s lymphomas are heterogenous diseases. The number of localized PGL allowed for detailed analyses. Larger studies are needed for stages III and IV and for intestinal NHL. Although this is a retrospective study, a stomachconserving approach may be favored. Key Words: Gastrointestinal neoplasms NHL Gastrointestinal lymphoma Prognostic factors Survival. Correspondence: Dr Hanan Shawky Gamal El-Deen, Clinical Oncology Department, Faculty of Medicine, Tanta University Hospital, hannshawky@yahoo.com INTRODUCTION Gastrointestinal tract is the most common site for the development of extra nodal lymphoma []. Primary gastrointestinal lymphomas constitute to of all gastrointestinal tumors [,]. Primary gastric NHL represents more than half of all PGI NHL in the western world and an increasing incidence has been reported []. Twenty percent to of PGI NHL, are primarily located in the intestine and differ from PGL in clinical features, pathology, treatment, morbidity and prognosis [-7]. There are at least two definitions of primary GI NHL in use. The one by Dawson et al. [8] is restricted to localized disease (stages IE, IIE), whereas that by Lewin et al. [9] requires that patients exhibit GI symptoms or predominant lesions in the GI tract. Several different histologic classifications have been published over the years, the WHO classification has been updated in the past years and published in September 8, it builds upon the advances of the past and makes some inroads into better defining heterogeneous or ambiguous categories of disease []. However, for most studies on PGI NHL, the Working Formulation or the Kiel classification had been applied [,], but the mucosa-associated lymphatic tissue (MALT) concept published by Isaacson et al. [], which for the first time classified extranodal lymphomas, had not been widely used or was applied retrospectively during the last years. Although Musshoff s modification of the Ann Arbor staging classification is applied in most series [], special

2 Primary Gastrointestinal Non-Hodgkin s Lymphoma classifications for staging of PGL were published and used by other authors [,-7]. Treatment strategies in nodal NHL are well established, but there still remains much debate and controversy regarding the optimal approach in GI NHL, particularly in PGL. Surgery, radiotherapy and chemotherapy have been used alone or in various combinations [8-]. The objective of this retrospective study was to describe the clinical presentation and to get information about anatomic and histologic distribution, epidemiologic data, initial complications, morbidity, mortality, prognostic factors and treatment results for these diseases within a standardized diagnostic and therapeutic setting. Also, it was to answer some of the open questions particularly the question of treatment results after combined surgical and adjuvant treatment or conservative treatment alone for PGL patients in stages IE and IIE. PATIENTS AND METHODS Patients: From January 997 through January 7, every patient with a PGI NHL reported in the Clinical Oncology Department, Tanta University Hospital was considered eligible to evaluate the clinical features of this disease. PGI NHL were defined according to Lewin et al. [9]: Patients had to present with GI symptoms or predominant lesions in the GI tract. Intestinal lymphomas were subdivided as follows: () duodenum, () small bowel, () ileocecal region, defined as involvement of terminal ileum, cecum, appendix and/or lower part of ascending colon, () colon and () rectum. We considered the ileocecal region and the rectum as separate sites, because they allow localized treatment in curative intention by localized RT or resection. Besides gastric and intestinal lymphomas, a third group was distinguished that included patients whose NHL was diagnosed simultaneously at several GI sites. This group showed a very heterogeneous pattern in its presentation, with combinations of up to five regions, including the oral cavity. Simultaneous diagnosis of gastric and duodenal NHL was not considered as MGI but as continuous growth from the stomach. We decided to perform a retrospective study because, for intestinal lymphoma, the scarcity of the disease would not allow the accrual of enough patients for a valid statistical analysis in a prospective study. Also, confronted with conflicting opinions of physicians, as in gastric lymphoma, the question of choice between combined surgical and conservative or conservative management only gave rise to serious doubts about its acceptance by physicians and hence the resulting patient accrual, thus we decided to do this retrospective study rather than strive for a randomization between surgical and non-surgical treatment strategies. Acceptance of this concept was quite satisfying, resulting in an analysis of patients with primary gastric NHL as detailed in this report. Protocol radiotherapy and/or chemotherapy was obligatory and stratified according to histologic grading, stage of disease and whether surgery had been carried out or not. Eleven patients (who were older than 7 years and/or presented with second malignancies, had missing confirmation of histologic subtype, or had comorbidity prohibiting therapy were not included in the evaluation of treatment results. Another patients could not be evaluated for the following reasons: No remissioninducing treatment given (n=), patient s refusal of therapy (n=), or insufficient data (n=). For evaluation of histologic and clinical features, these patients were included. A total of 9 patients were eligible for the analysis of treatment results. Diagnostic and staging procedures: The diagnostic work-up included patients history and physical examination. Blood tests done such as lactate dehydrogenase, liver enzymes, alkaline phosphatase, creatinine, urea and complete blood count. In addition to chest X-ray, bone marrow biopsy, radiologic and endoscopic evaluation with multiple biopsies of the upper and lower GI tract, abdominal ultrasound and computed tomography of chest and abdomen. Formalin-fixed specimens were reviewed according to the classification by Isaacson et al. [7] and the revised Kiel classification [], especially with regard to simultaneous lowgrade component (SLGC) in high-grade lymphomas. Some biopsies were investigated immunohistochemically by staining for CD.

3 Patients were staged according to the Ann Arbor classification in its modification by Musshoff []. In cases of tumor resection, the extent was analyzed retrospectively based on operating sheets and histopathologic reports. Follow-up and statistical analysis: The date of this analysis was October st, 8. The median time of follow-up was 89. months (range from 7. to.7 months) from the first day of treatment. Response criteria and end points were reported according to published guidelines [8]. Evaluation of treatment-related toxicity was performed according to the Standard WHO toxicity criteria [9]. Restaging after completion of treatment included diagnostic endoscopy and biopsies of the primarily involved site, abdominal and pelvic computed tomography scan and/or ultrasound, chest X-ray, blood tests as described above and clinical examination as well as patient history. Follow-up evaluation consisted of history, physical examinations, chest X-ray, endoscopy and abdominal ultrasound. Additional tests were carried out if necessary. Patients were examined at least every months for years and then twice a year afterwards. SPSS [Statistical package (version.)] was used for data analysis. Mean and standard deviation were estimates of quantitative data. Chi-square/Fischer exact were tests of proportion independence. Kaplan-Meier [] method was used for estimating survival and log rank to compare curves. p value was significant at. level. RESULTS Patient characteristics: From January 997 through January 7, we studied 8 patients 9 to 8 years old (mean age, 9. years) with biopsy-confirmed PGI NHL who were treated at the Clinical Oncology Department, Tanta University Hospital. Four main sites of origin for GI NHL could be distinguished at diagnosis. The most frequent location was the stomach (7.). The second largest group was lymphoma originating in the small bowel (8.), followed by those of the ileocecal region (7.). Isolated involvement of the duodenum was very scarce (two of 8). The same applies to lymphoma of the colon Hanan Shawky & Hesham Tawfik (two of 8). Localized growth, originating in the rectum developed in four of 8. MGI involvement as defined in patients and methods occurred in. of the cases. Pain was the main diagnostic symptom in most cases (7), followed by loss of appetite in (). Constipation and ileus were more frequently encountered in intestinal lymphoma and considered as diagnostic symptoms for the intestine when combined as signs of occlusion. Occult loss of blood or macroscopic bleeding was most frequent when the stomach or the ileocecal region were involved. Perforation was scarce (only case in gastric and cases in NHL of the small intestine) (Table ). Median time from onset of symptoms to diagnosis was the shortest for ileocecal lymphoma (7 days) and longest for multiple GI involvement ( days). The patient characteristics and clinical features of all patients are listed in Table (). There was just a slight predominance of the male sex for gastric lymphoma (.:) as compared to NHL of the small intestine (.8:) and especially those of the ileocecal region (.7:). The median age was similar in patients with gastric and multiple GI sites ( years), but differed from patients with small intestinal lymphoma, ( years), (standard deviation ±.) and was markedly lower for cases with ileocecal NHL (7 years). This last group also had the best performance status (9. with ECOG performance status [] ), which was also good in the total patient population (>8 with ECOG performance status ). Lactate dehydrogenase level, was elevated in approximately 9 of patients. Gastrointestinal non-hodgkin s lymphomas as such can be considered as a localized disease, with the exception of multiple GI involvement (Table ), Stages III and IV were about. A slight tendency for higher spread could be noticed in NHL of the small bowel, compared with gastric and ileocecal lymphoma, of which more than 7 were diagnosed in the very localized stages IE and II E. We were able to demonstrate that the recommendation by Musshoff et al. [] to divide stage IIE into stage II E (involvement of regional lymph nodes only (gastric/mesenteric) and stage II E [involvement of distant lymph nodes (para-aortic/para-caval)]

4 Primary Gastrointestinal Non-Hodgkin s Lymphoma reflected a significant difference in DFS as well as in OS (all p=<.). Involvement of nonlymphatic or non-gi sites occurred in patients (stages IVE). The most frequently involved sites was the bone marrow (n=7), followed by the liver (n=). In three cases, the lung was involved. Histologic subtypes: In general, high grade subtypes accounted for the majority of GI lymphoma (including Burkitt s, lymphoblastic and T-cell lymphomas). A more differentiated analysis of histologic subtypes revealed a distinguishable pattern in the sites of involvement (Table ). In gastric lymphoma, were of lowgrade MALT type. In about one third of the high-grade gastric lymphomas, a simultaneous low-grade MALT-type component could be demonstrated. Low-grade non-malt-type NHL (mantle-cell lymphoma) as well as Burkitt s and lymphoblastic lymphoma were small in numbers (. and., respectively). In the intestinal lymphoma, most NHL were of high grade lymphoma, although there was a distinct difference between the small bowel and the ileocecal region. There were no Burkitt s or lymphoblastic NHL in the small bowel, whereas only one T-cell NHL occurred in the ileocecal region. Numbers of MALT-type lymphoma were small in both regions. When multiple GI sites were involved, low-grade lymphoma, mostly of MALT type, had the highest frequency (.8). Invading growth into neighboring organs was found in nearly of the cases. It was more frequent among high-grade and high-grade with low-grade MALT-type component than among low-grade lymphomas [. (/8), 7. (/) and.9 (/77), respectively]. As regards the distribution of histologic subtypes according to the stage, it was found that in contrast to nodal NHL, the majority of low-grade GI lymphomas were in stage IE, whereas high-grade as well as secondary highgrade NHL showed a higher fraction in more advanced stages (II E and II E). They also had a higher tendency to invade neighboring organs as mentioned above. Treatment: Seventeen patients were not included in the assessment of treatment results as mentioned in patients and methods. A total of 9 patients were eligible for the analysis of treatment results. The median follow-up time of the complete cohort was 89. months (standard deviation ±.) from the onset of treatment (range from 7. to.7 months). The DFS and the OS of the patients in the four major groups of GI NHL are shown in Figs. (,). Gastric and ileocecal lymphoma showed a higher DFS and OS as compared to NHL of the small bowel (DFS, p=. and p=.9, respectively) and when compared to the situation where multiple GI sites were involved (DFS, p=<. and p=., respectively), as shown in Figs. (,). The OS at years for all intestinal lymphomas together was. compared to 8. for patients with gastric lymphoma. The OS proportions at years are listed in Table (). Age (p=.) and sex (p=.9), did not influence OS. ECOG performance status > (p=.), advanced stage (p=<.), high grade tumors (p=<.) and elevated LDH (p=<.) reduced significantly OS. The DFS proportions at years according to tumor stage, site of origin and histology are shown in detail in Table (). One hundred and eight primary events, defined as relapse, or death owing to any cause, have been observed. Fifty-nine patients experienced relapse, but salvage therapy was successful in cases. Forty-nine patients died, (9 deaths related to treatment, whereas in 9 patients, other causes (second malignancies, n=; cardiac dysfunctions, n=8; status asthmaticus, n=; renal failure, n=7; liver impairment, n=9) were obvious occurrence 7. to 7 months after start of treatment. Only one patient died after perforation. The acute reactions of different grades according to the Standard WHO toxicity criteria [9] attributable to the chemotherapy included leukopenia (< white cells per microliter) in of the patients, oral ulcers in 9, alopecia in, diarrhea in, nausea and vomiting in 7. The acute reactions attribut-

5 able to chemotherapy combined with radiotherapy of different grades included diarrhea in 7, bladder irritation in, fatigue in and leukopenia in. There were 9 deaths attributable to treatment related toxicity. The percentages of patients sustaining a toxicity during treatment of grade or more, wrether hematological (leukopenia, thrombocytopenia, neutropenic fever), genito-urinary or GIT (nausea/vomiting, or diarrhea) are shown in Table (). There were no acute grade events. The percentage of patients sustaining late morbidity reported during the follow-up period of this study was shown in Table (). All but one of the late toxicities have resolved with subsequent treatment and follow-up. In one patient, a grade GIT reaction persisted. There was a striking difference in the pattern of relapse in stages IE and IIE gastric lymphoma cases depending on whether surgery had been performed or not. After partial or complete resection, patients out of 7 () relapsed; had a systemic relapse, had a local relapse and had regional nodal relapse. In conservatively treated patients, lymphomas out of relapsed cases () relapsed locally and salvage treatment, which consisted of eradication of H. pylori, administration of second line chemotherapy, or surgery, was successful in all these cases. The median time in second complete remission for relapsed conservatively treated patients was. months (range,. to.7 months). The conservative treatment of early stages (IE and IIE) PGL is an alternative to the established and long-favored surgical approach. There were no differences in OS (OS was 8. for patients who underwent conservative treatment only compared to 8.7 for patients who had surgery as part of their treatment strategy (p=.). In univariate and multivariate analysis the extent of tumor resection in stages IE and IIE gastric lymphoma cases proved to be independently of significant prognostic value. After complete resection, the survival proportions for DFS and OS at years were both as compared to 7. after incomplete resection (both p=<.). Also, one has to keep in mind that in patients whose lymphoma was resected radically, prognosis is significantly better than Hanan Shawky & Hesham Tawfik after conservative treatment only (p=<.). On the other hand, relapses, which occurred after chemotherapy and/or radiation only, were usually localized in the stomach and therefore could be treated easier than in case of a systemic relapse. Results for patients with lymphomas originating in the remaining sites (duodenum, colon, or rectum) were only described because of their small numbers. All three patients with rectal lymphoma reached a complete remission (CR), none experienced relapse and all were alive between and 8 months of follow-up. The patient with NHL of the colon was in an ongoing CR at 7 months. The patient with a lymphoma of the duodenum relapsed after 8 months and died after 7 months of follow-up period. Considering the extent of disease, stage was prognostic (p=<.) in PGL patients (Figs.,). DFS and OS in stages IE and IIE were significantly longer compared with stages IIIE and IVE (DFS at years was 8 and 7., respectively, while -year OS was 8. and 7. respectively, all p=<.). The median DFS time in stages IIIE and IVE was. months (standard error ±9.). Medians for DFS or OS were not reached in stage IE/IIE patients. In our series there is a high significance (p<.) comparing DFS and OS in stages IE and II E to stages II E to IVE (DFS at years was 88.7 and.8, respectively, while -year OS was 9.7 and. respectively). The grading of PGL patients was prognostic for OS and DFS (Figs.,). Regarding DFS and OS, high-grade lymphoma with low-grade components had a significantly worse outcome as compared to low-grade lymphoma (p= <.). We could not detect any statistical significant influence of stage or histologic subtype in the intestinal NHL. This was due to the small numbers within the different sites of origin. In the NHL of the small bowel, seven of eight relapsed cases had high-grade NHL. In the ileocecal region, there were one low-grade NHL and one T-cell lymphoma, none of which relapsed, whereas the failure rate in high-grade and Burkitt s/lymphoblastic NHL was approximately. In lymphomas originating at multiples sites of the GI tract, three of seven low-grade NHL relapsed while all of the six high grade NHL relapsed.

6 Primary Gastrointestinal Non-Hodgkin s Lymphoma Table (): Clinical picture at diagnosis in patients with PGI NHL (Major sites only, n=). Symptoms and signs (n=) Small bowel (n=7) Ileocecal region (n=) Multiple GI sites (n=) Total number of patients Pain Loss of appetite Loss of weight Bleeding Vomiting Night sweats Diarrhea Constipation Fever Perforation Ileus B symptoms (fever, night sweats and loss of weight) Table (): Patient characteristics and clinical features in patients with PGI NHL (Major sites only, n=). Clinical feature (n=) Small bowel (n=7) Ileocecal region (n=) Multiple GI sites (n=) Total number of patients Sex: Female Male Age, years: Median 7 ECOG performance status []: LDH (normal range U/L) Elevated Stage: IE II E II E IIIE IVE Table (): Distribution of histologic subtypes in PGI NHL. Types of lymphoma Small bowel Ileocecal region Multiple GI sites Duodenum (no.) Colon (no.) Rectum (no.) Low-grade non-malt type Low-grade MALT type High-grade with low-grade MALT-type component High-grade Lymphoblastic or Burkitt s T-cell

7 Hanan Shawky & Hesham Tawfik Table (): Overall survival (OS) proportions at years according to patients and tumor characteristics. Sex: Male Female Age: < years years ECOG performance status [9]: > LDH: Normal Elevated Stage: IE II E II E IIIE IVE Histology: Low-grade MALT type High-grade with low-grade MALT-type High-grade Lymphoblastic or Burkitt s GI site: Ileocecal region Small bowel Multiple GI sites p-value was significant at.. OS () p value.9.. <. <. <.. Table (): Disease free survival (DFS) proportions at years according to tumor characteristics. Stage: IE II E II E IIIE IVE Histology: Low-grade MALT type High-grade with low-grade MALT-type High-grade Lymphoblastic or Burkitt s GI site: Ileocecal region Small bowel Multiple GI sites p-value was significant at.. DFS () p-value* <. <. <. Table (): Acute and late grade III and IV treatment-related toxicity (n=9). Toxicity Hematological GIT Bladder Other Hematological GIT Cum survival Acute treatment-related toxicity Grade III toxicity Grade IV toxicity Late treatment-related toxicity Grade III toxicity Grade IV toxicity.. Fig. (): Disease free survival (DFS) in PGI NHL according to anatomic site. Cum survival DFS (months) Tumor sites > GIT site Ileocaecal region Tumor site > GIT site Ileocaecal region Small intestine Small intestine OS (months) Fig. (): Overall survival (OS) in PGI NHL according to anatomic site.

8 Primary Gastrointestinal Non-Hodgkin s Lymphoma Cum survival.... Stage IE II E II E IIIE IVE p<. Cum survival.... p<. Histopathological type High grade High grade & low grade MALT Low grade MALT Low grade non MALT Lymphoblastic or Burkitt s DFS (months) Fig. (): Disease free survival (DFS) in PGL patients as stratified by stage OS (months) Fig. (): Overall survival (OS) in PGL as stratified by histologic subtype. Cum survival Stage IE II E II E IIIE IVE p< OS (months) Fig. (): Overall survival (OS) in PGL patients as stratified by stage. Cum survival p<. Histopathological type High grade High grade & low grade MALT Low grade MALT Low grade non MALT Lymphoblastic or Burkitt s DFS (months) Fig. (): Disease free survival (DFS) in PGL as stratified by histologic subtype. DISCUSSION In the PGI NHL, the stomach is the most common site of involvement, ( to 8 of all cases of GI lymphoma) [,-7], with the exception of two studies showing a lower frequency of gastric lymphoma (7.8 [9] and. [8], respectively). In our series of 8 patients registered retrospectively, the stomach was the main site in approximately 7 of cases, which was clearly higher than in many other published series [,,,9,]. A pathologic referral center reported the highest rate (8), although only stages IE and IIE were considered []. Single-institution data ranged from 7.8 to. [9,,]. The difference between the reported series is difficult to interpret. The reasons could be many-fold. All but one study [] were carried out retrospectively and the period of recruitment ranged from to years. Both facts suggest possible mechanisms of selection in the reported cohorts. Selection by treatment intentions might also be of influence, as one author discussed for his series [8]. In comparison with the policy of our study group, which offered the inclusion of surgical and organ-preserving treatment, another study with the primary aim of resection would inevitably not register conservatively treated patients []. Another factor that influenced the reported rates for the different GI sites was whether children had been included in an analysis [,,9,]. In some series, simultaneous involvement of different GI sites was not reported as a separate entity [9,,].

9 8 It therefore remains uncertain whether it was not diagnosed in the first place or was classified as primary gastric or primary intestinal lymphoma. This represented another reason for a possible variability in the stated rates for GI NHL. Within the lymphomas of the intestine, two main sites were distinguished in the literature, the small bowel and the colon. Further differentiation within these two groups was used very nonuniformly [,9,-,8-,]. In six of the cited publications, the ileocecal region was distinguished from small bowel and colon, as we did in our analysis [,9,,,,8]. For these reasons, the rates of primary sites within the intestine vary considerably. This was especially noticeable for lymphoma of the ileocecal region. The data ranged from.9 in the largest series [] and 9. in another study from Great Britain [8] to 8. (/) in our report. The range in the remainder of the cited publications was. to. [,9,,]. The main reason for these differences was probably a question of the definition of the ileocecal region, which was missing in most reports. To describe the extent of the disease, most authors applied the Ann Arbor classification or its modification [-]. Localized stages (IE, IIE) are predominant in gastric lymphoma. Two authors reported 8 and 87 [,], which were comparable to our data (89.7), whereas another published registry data were lower (8) []. The rate for localized intestinal lymphoma was slightly lower, with a range of to 8 []. Only one study stated the distribution of stages in different sites of intestinal lymphoma [] and reported a percentage in localized disease (stages IE and IIE) of 78 for the small bowel and 8 for the ileocecal region which was lower than that reported in our series (8. and 9., respectively). Other studies, which applied the Manchester staging system [], published rates of less than for the stomach as well as for the intestine []. This was also in contrast to two other studies, which stated 7 and 7 for PGI NHL in localized stages as a whole [8,] which was lower than that reported in our series (8.). In our study, the DFS and OS at years for the combined stages IE and IIE PGL patients were 8 and 8. respectively. Sano et al. Hanan Shawky & Hesham Tawfik [7] reported an OS at years of 8. for stages IE and IIE in a single-center study, which was comparable to the results published in other reviews [8,9]. Extended disease (stage IIIE, IVE) was reported nonuniformly. Some authors [] applied the Lugano classification (which unites stages IIIE and IVE as stage IVE) [], included stage II E in their definition of extended disease because treatment results were thought to be the same as in stages IIIE and IVE and reported that stage is prognostic (p=.) without stating a survival proportion. In our series there was a high significance (p<.) comparing stages IE and II E to stages II E to IVE (DFS at years, 88.7 and.79, respectively, while -year OS was 9.7 and. respectively). Otter et al. [9] reported an OS at years of (stages IIIE and IVE); Morton et al. [8] stated approximately. Combining stages IIIE and IVE in our study, the OS at years was 7.. Independent of the definitions of advanced disease, all [9,,,,] but one [8] study stated a worse prognosis for this group of patients. Morton et al. [8] did not find a difference but discussed treatment selection as a possible cause. The majority of PGI NHL was of high grading in all series, but the usage of different histologic classifications made a comparison difficult. To our knowledge, there was no published major prospective randomized study applying the classification of Isaacson et al. [] especially with regard to simultaneous lowgrade component (SLGC) in high-grade lymphomas, but this was done in retrospective analyses based on resection specimens [,], however both reports were restricted to localized gastric lymphoma. Both studies reported a significantly higher survival rate at years for low-grade lymphoma (9 [] and 7 [], respectively) as compared to high-grade NHL ( [] and [], respectively), although their results for patients with SLGC in highgrade lymphomas were contradictory. In the report by Cogliatti et al. [], the survival rate in these patients was 7 at years, with no difference as compared to high-grade NHL at years. In the publication by Radaszkiewicz et al. [], there was no difference in the survival rate between low- and secondary high-grade NHL.

10 Primary Gastrointestinal Non-Hodgkin s Lymphoma In our study, we found a significant difference in survival rates between low- and highgrade PGL in DFS and OS (at years DFS and OS for low-grade lymphoma were both 98. compared with. and 7.9 respectively, for high-grade NHL). The DFS and OS were significantly worse for patients with high-grade with low-grade MALT-type component (7.8 and 8.77 respectively), compared to low-grade MALT-type NHL (both were 98.). In our series of primary GI NHL, the site of origin was prognostic in the four major groups. Multiple GI sites had the worst outcome, with a median survival of. months and an OS at years of.7. This was 7 in the French series [] and was even poorer in the only other data published by d Amore et al., on MGI (median survival,.7 years; OS at years, 7) []. For primary NHL of the small intestine, the OS at years was. in our study compared to 7 in another major series []. Most publications had just stated an OS for all intestinal lymphomas together, with a range of to 7 [], which was. in our series. A more detailed analysis, concerning stage and histologic subtype, was impossible because of diverging definitions as mentioned above, small numbers in most series and different histologic definitions. Gastric lymphomas have a comparatively good treatment outcome, although data varied again for the aforementioned reasons. The highest rates for OS at years were reported from our study (8.) and by the French group (9) []. As regards the analysis of treatment results, in our study, the extent of resection was prognostic. DFS and OS were significantly better after complete removal of the tumor (the DFS and OS at years were after radical resection compared to 7. after incomplete resection). The results reported by Ruskoné- Fourmestraux et al. [] underlined the importance of a complete resection, the -year OS was after radical resection as compared to when the lymphoma was not resected or was incompletely resected, that confirmed the review of the literature by Azab et al. []. In early stages (IE and IIE) PGL, although both treatment groups in our study were not randomized, we think with due caution that a 9 comparison was justified. There were no differences in OS (OS is 8. for patients who underwent conservative treatment only compared to 8.7 in patients who underwent surgery as part of their treatment strategy). With respect to our data, the conservative treatment of early stages (IE and IIE) PGL was an alternative to the established and long-favored surgical approach. However, because this was a retrospective study, results should be interpreted with due caution. In summary, GI NHL is a heterogeneous disease depending on the site of origin within the GI tract, which is a prognostic factor. Primary gastric lymphoma is by far the largest group, which has its own distinct histopathologic and clinical features. Stage is one of the most important prognostic factors, with a significantly better survival for localized disease. The frequency of gastric lymphoma in stages IE and IIE allows an analysis of the treatment strategy concerning combined surgical and adjuvant treatment versus conservative treatment alone. Although this was a retrospective study, a stomach-conserving approach might be favored. Numbers of intestinal lymphoma were too small for subanalyses and did not allow better comparison, thus, it seems that intestinal lymphomas should get more interest in the future and become the aim of large prospective studies. Finally, a uniform reporting system for PGI NHL, in terms of definitions and histologic and staging classifications, is needed to facilitate comparison of treatment results. REFERENCES - Shukla K, Patel T, Shukla J, Palanki S. Primary gastrointestinal lymphoma-a clinicaopathologic study. Indian J Pathol Microbiol. 7, (): Radaszkiewicz T, Dragosics B, Bauer P. Gastrointestinal malignant lymphomas of the mucosa-associated lymphoid tissue. Factors relevant to prognosis. Gastroenterology. 99, : Domizio P, Owen RA, Shepherd NA, Talbot IC, Norton AJ. Primary lymphoma of the small intestine: A clinicopathological study of 9 cases. Am J Surg Pathol. 99, 7 (): Al-Akwaa AM, Siddiqui N, Al-Mofleh IA. Primary gastric lymphoma. World J Gastroenterol., : -. - Koch P, Liersch R, Berdel WE. Intestinal Non- Hodgkin s Lymphoma. J Clin Oncol., (): 7-.

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